tbuckley/cabot-search huggingface dataset:
The adjuvant oxaliplatin-irinotecan paradox.
Authors: James David Mackey, Peter Young, Richard Preble, Brittany Miles
Journal: Journal of Clinical Oncology (2023)

e15655 Background: A pervasive pattern in oncology is that chemotherapeutic agents which achieve acceptance for adjuvant use are the ones that have shown superior efficacy in the treatment of metastatic disease. The greater the efficacy in metastatic disease, the greater the likelihood that adjuvant use will be statistically viable. Oxaliplatin is the exception to this, having paradoxically shown similar outcomes to irinotecan in metastatic colorectal cancer (CRC) but superiority in the adjuvant setting. In this study, the TriNetX research database was used to better evaluate the adjuvant efficacy of oxaliplatin use in real-world patients. Methods: The TriNetX research database was used for this study. The TriNetX platform provides access to anonymized medical record information on more than 91 million patients in 75 large healthcare organizations. Three cohorts of stage III colorectal patients were created for comparison, utilizing International Classification of Disease-10 (ICD-10) codes and medication codes provided in the TriNetX platform. All patients were required to have a diagnosis of colon cancer (C18) and lymph node involvement (C77), with the absence of any liver or lung metastases (C78.7 and C78.0, respectively). Adjuvant oxaliplatin use was identified by the presence of the oxaliplatin medication code within 9 months of CRC diagnosis. The adjuvant oxaliplatin cohort was compared to a cohort with no oxaliplatin exposure, identified by the exclusion of the oxaliplatin medication code for 12 months following CRC diagnosis. The cohorts were balanced for age, race, gender, and ethnicity. The endpoint of the comparisons was all-cause mortality at 5 years. Results: Adjuvant use of oxaliplatin was associated with a 2.3% absolute decrease in the risk of death at 5 years (risk ratio 0.88, 95% CI (0.79,0.97), p-value 0.01). See figure 1. Conclusions: This study shows that adjuvant use of oxaliplatin is associated with a 2.3% absolute survival advantage in stage III colorectal cancer patients. This small absolute benefit is likely why occasional retrospective analyses have been unable to replicate it. A controlled interrupted time series analysis from Huang, et. al. showed no benefit to adjuvant oxaliplatin in the stage III setting for Taiwanese patients. Such a small benefit may also explain why the ACHIEVE trial found three months of adjuvant oxaliplatin to be equivalent to six. When a benefit is very small, a shorter duration of treatment would be more likely to result in statistical equivalency than if the benefit was more substantial. [Table: see text]
Sintilimab plus gemcitabine and cisplatin as a first-line treatment for patients with advanced biliary tract cancer: A biomolecular exploratory, phase II clinical trial.
Authors: Zhen-gang Yuan, Tian-mei Zeng, Guang Yang, Cheng Lou, Wei Wei, Chen-jie Tao, Xi-yun Chen, Qin Han, Zhuo Cheng, Pei-pei Shang, Yu-long Dong, He-ming Xu, Lie-ping Guo, Dong-sheng Chen, Yunjie Song, Chuang Qi, Wanglong Deng
Journal: Journal of Clinical Oncology (2023)

4086 Background: The prognosis of biliary tract cancer (BTC) remains unsatisfactory. Thus, this study aimed to determine the efficacy, safety, and predictive biomarkers of the immune checkpoint inhibitor sintilimab in combination with gemcitabine and cisplatin (GemCis) in advanced BTCs. Methods: In this single-arm, phase II study (Trial registration number: ChiCTR2000036652), gemcitabine (1000 mg/m²) plus cisplatin (25 mg/m²) were administered on days 1 and 8, respectively, while 200 mg sintilimab was administered on day 1 of each 21-day cycle for 6–8 weeks, followed by sintilimab alone up to 2 years. The primary endpoint was overall survival (OS). The second endpoints were objective response rate (ORR), progression-free survival (PFS), and disease control rate, assessed using RECIST V.1.1. Multiomics biomarkers associated with clinical response were assessed as exploratory objectives. Results: Thirty patients were enrolled between August 2020 and May 2022. The median follow-up duration, OS, and PFS were 12.3 months (95% confidence interval [CI]: 9.1–16.0), 15.9 months (95% CI: 8.6–not reached), and 5.1 months (95% CI: 4.3–8.7), respectively. Here, 36.7% of patients were found to achieve an objective response. The most common grade 3 or 4 treatment-related adverse events were thrombocytopenia (33.3%), with no reported deaths nor unexpected safety events. Biomarker analysis indicated that patients with homologous recombination repair pathway gene alterations (median, PFS: 9.8 vs. 4.5 months, p = 0.023; OS: NR vs. 9.0 months, p = 0.014; ORR: 77.8% vs. 19%, p = 0.004) or loss-of-function mutations in chromatin remodeling genes (median, PFS: 8.7 vs. 4.2 months, p = 0.021; ORR: 63.6% vs. 21.1%, p = 0.046) presented better tumor response and survival outcomes. Furthermore, transcriptome analysis of the tumor immune microenvironment revealed a markedly longer PFS, and tumor response were associated with higher expression of 3-gene effector T cell signature (median, PFS: 7.8 vs. 4.3 months, p = 0.02; ORR: 64.2% vs. 7.1%, p = 0.004) and 18-gene inflamed T cell signature (median, PFS: 8.6 vs. 4.3 months, p = 0.01; ORR: 64.2% vs. 7.1%, p = 0.004). Moreover, our findings highlighted the adverse predictive value of mast cells in immuno-chemotherapy for BTCs for the first time. Conclusions: Sintilimab plus GemCis displayed a promising antitumor activity and acceptable safety profile as a first-line treatment in patients with advanced BTC. Multiomics potential predictive biomarkers are identified and warrant further verification. Clinical trial information: ChiCTR2000036652 .
Landscape of FGFR2/3 alterations in genitourinary cancer.
Authors: Xiangyu Che, Huanhuan Liu, Jiayue Qin, Shanbo Cao
Journal: Journal of Clinical Oncology (2023)

e15047 Background: FGFR2/3 is frequently activated by mutation or overexpression, and it is a validated therapeutic target in several cancers. However, the molecular profile of FGFR2/3 in genitourinary cancer is still lacking. In this study, we assessed FGFR2/3 alterations for better understanding therapeutic implications in genitourinary cancer. Methods: Patients diagnosed with genitourinary cancer were enrolled in the study. Tumors and plasma samples of participants were sequencing for next-generation sequencing from Chinese cohort and TCGA database. Results: A total of 3858 patients were enrolled with 1640 renal cell cancer (RCC), 1300 prostate cancer (PC), and 918 urothelial cancer (UC), containing 2482 tumor tissues and 1376 baseline plasma samples were collected. A total of 14.6% patients (563/3858) harbored at least one FGFR2/3 alterations . 24.1% (221/918) UC carried the most FGFR2/3 alterations , including somatic mutation (18.2%), CNV (5.7%), and fusion (2.1%). Furthermore, the altered FGFRs targets are mainly S249C (6.5%), Y373C (2.5%), FGFR3-TACC3 fusion (1.6%). R248C (1.2%), and G370C (0.5%) in UC. FGFR2/3 alterations were found in 14.0% (182/1300) PC, including somatic mutation (8.2%), CNV (5.8%), and fusion (0.4%). However, only 2 patients were found to have altered FGFRs targets including R248C mutation and FGFR3-TACC3 fusion (n = 1 each). Regarding of RCC, only 9.8% (160/1640) patients had FGFR3 alterations , including somatic mutation (5.8%), CNV (5.0%), and fusion (0.5%). Furthermore, the altered FGFRs targets are mainly R248C, S249C, Y373C (n = 4 each). Moreover, patients with FGFR2/3 alterations harbored a significantly higher TMB than those in patients without FGFR2/3 alterations (Mean: 13.3 vs 9.4; p &lt; 0.001). There was a significant difference in TMB among different cancers with FGFR2/3 alterations , with UC being the highest and PC the lowest (Mean: 17.0 vs 13.0 vs 10.2; p &lt; 0.001). Conclusions: FGFR2/3 alterations are frequently altered in genitourinary cancer, especially UC. Comprehensive genomic profiling of FGFR2/3 alterations highlights the clinical and therapeutic implication.
Association between food insecurity and frailty among older adults with gastrointestinal malignancies: The CARE Registry.
Authors: Mackenzie Elisha Fowler, Christian Harmon, Noha Sharafeldin, Smith Giri, Grant Richard Williams
Journal: Journal of Clinical Oncology (2023)

12046 Background: Food insecurity is associated with higher gastrointestinal (GI) cancer mortality, but its association with frailty, a known predictor of premature mortality among older adults with cancer, is less understood. Our objective was to evaluate the association between food insecurity and frailty among older adults with GI malignancies. Methods: In this cross-sectional analysis, we included 424 older adults ≥60y recently diagnosed with GI cancer undergoing self-reported geriatric assessment (GA) at their first pre-chemotherapy visit to the University of Alabama at Birmingham oncology clinic. Food insecurity was the exposure of interest, defined using the 2019 United States Department of Agriculture Economic Research Service (USDA ERS) Low-Income, Low-Access (LILA) measure, which classifies census tracts based on income and/or access to food stores at various distances by urban-rural status. The primary outcome was frailty measured via the CARE Frailty Index, a composite measure based on the proportion of deficits across several GA measures (44 items in total). Frailty was dichotomized as frail or robust/pre-frail. We examined the association between LILA and frailty with modified Poisson regression accounting for census tract clustering. Results: Median age at study participation was 69 (IQR: 64, 76), 56.6% were male, 27.2% were non-Hispanic black, 31.4% had colorectal, 28.1% had pancreatic cancer, and 71.7% presented with stage III/IV disease. LILA versus non-LILA had a higher proportion of participants who were non-Hispanic Black (52.1% vs. 11.0%, p: &lt; 0.001) and lower educated (high school or less: 50.6% vs. 35.0%, p: 0.020). After adjustment for age, race, sex, cancer type and stage, LILA was associated with 37% higher risk of frailty (RR: 1.37, 95% CI: 1.05, 1.80) versus non-LILA. Analysis of LILA sub-categories revealed that the overall effect may be driven by low income + low access at 1 mile for urban/10 miles for rural areas (RR: 1.47, 95% CI: 1.12, 1.94) and low income + low access at 0.5 mile for urban/10 miles for rural areas (RR: 1.39, 95% CI: 1.05, 1.85). Low income + low access at 1 mile for urban/20 miles for rural areas, low income + low access with a vehicle or at 20 miles, low income only, or low access only did not demonstrate a significant difference. Conclusions: Low income and low access to food stores is associated with higher risk of frailty among newly diagnosed older adults with GI cancers prior to systemic treatment. Intervening on food insecurity at the local level, particularly in areas with low income and low access, may be a target for improving rates of frailty among older adults with GI cancers. Future studies are needed to determine causality.
Physician-reported barriers and strategies to using tumor mutational burden (TMB) testing in oncology care: An interview based study.
Authors: Gieira S Jones, Elizabeth A. Szamreta, Liam Lee, Radhika Iyer, Bianca Jackson, Ning Ning, Jennifer Stephens, Arif Hussain
Journal: Journal of Clinical Oncology (2023)

e15063 Background: Despite the availability of genomic technologies to inform treatment for oncology patients, widespread adoption of genomic testing in the U.S. has been challenging. Little information is available about the factors that influence clinical decision making regarding the use of TMB testing. The purpose of this study was to identify barriers to the adoption of TMB testing and preferred strategies to increase testing from the physician’s perspective. Methods: Semi-structured video-based interviews were conducted with a sample of U.S. physicians (N = 11), including 6 general medical oncologists, 3 surgical oncologists, and 2 gynecologic oncologists. Physicians were asked about practice characteristics, perceived barriers to testing, and potential strategies for alleviating these barriers. Results: Eighty-two percent (N = 9) of physicians reported utilizing TMB testing in their routine clinical practice. Reimbursement was the most commonly reported barrier (64%) including coverage policy language indicating the testing as “experimental”/“unproven”, patients having to pay out of pocket, and unclear/inconsistent payer policies (27% each) [Table 1]. Knowledge, resource-related, and logistical barriers were reported among the same proportion of physicians (45%). Suggested strategies to improve TMB testing uptake rates among physicians included better understanding of clinical utility of the test and corresponding therapies, integrating results into electronical medical records, incorporating TMB into routine testing, and shorter turnaround time for results. Conclusions: This qualitative study of physicians identified barriers to TMB testing of oncology patients. Results suggest that challenges around reimbursement, knowledge, resources, and logistics are key barriers to use of TMB testing for physicians. The findings of this study provide insights for future research and strategies to increase the adoption of TMB testing. [Table: see text]
Reversion of <i>RAS</i> mutations in metastatic colorectal cancer in the CCTG CO.26 clinical trial.
Authors: Florence T.H. Wu, James T. Topham, Christopher J. O'Callaghan, Harriet Feilotter, Hagen Fritz Kennecke, Kimberly Banks, Daniel John Renouf, Derek J. Jonker, Dongsheng Tu, Eric Xueyu Chen, Jonathan M. Loree
Journal: Journal of Clinical Oncology (2023)

3567 Background: RAS mutations in metastatic colorectal cancer (mCRC) drive resistance to anti-EGFR antibodies. It is unclear if RAS mutations are ever clonally lost, potentially uncovering a new therapeutic option for patients over time. Methods: We examined the temporal evolution of RAS mutation status among patients enrolled in CO.26 [ NCT02870920 ] – a phase II clinical trial that assessed durvalumab + tremelimumab in patients with heavily pretreated mCRC – using whole exome sequencing (WES) of archival primary tumor tissue and circulating tumor DNA (ctDNA) sequencing of serial plasma samples that were taken at baseline, week 8 and on progression. Results: Six out of 95 (6.3%) patients diagnosed with KRAS/ NRAS-mutated mCRC showed ‘neo- RAS-wildtype’ reversions at the time of baseline or week-8 ctDNA collection for the CO.26 trial. The majority (4/6) had falling tumor mutation burden (TMB) but stable or rising maximum mutation allele frequency (MAF) when reversions occurred. These were unlikely false negatives from non-secreting cancers as there were continued strong presence of other somatic clonal mutations (e.g., TP53, ATM). The majority (4/6) of reversions were transient, with mutations reappearing with progressive disease. ‘Neo- RAS-wildtype’ revertors had numerically longer median overall survival (OS) from date of cancer diagnosis to death compared those with persistent RAS mutations (7.7 vs. 4.2 yrs, HR = 0.65, 95% CI 0.31 to 1.36, log-rank P= 0.26). However, ‘neo- RAS-wildtype’ revertors were earlier-stage at diagnosis compared to those with persistent RAS mutations (33% vs. 63% had synchronous metastases, χ2 P= 0.15), and had lower disease burden upon enrollment (50% vs. 68.5% had liver metastases, P= 0.17; 33% vs. 75% had &gt; 4 lesions, P= 0.03*). Survival from stage IV diagnosis to death did not differ between those with reverted vs. persistent RAS mutations (median 3.8 vs. 3.2 yrs, HR = 0.77, 95% CI 0.35 to 1.72, P= 0.52). ‘Neo- RAS-wildtype’ reversions were not associated with side of primary tumors ( P= 0.41), archival BRAF/MEK/ERK-mutant status ( P= 0.16, 1.00, 0.09), baseline HER2 amplifications ( P= 1.00), or baseline TMB ( P= 0.21). Conclusions: We identified a 6.3% prevalence of ‘neo- RAS-wildtype’ reversions in the CO.26 trial, however only 2.1% of patients had persistent loss when serial time points were considered. Further research is needed to understand if ‘neo- RAS-wildtype’ revertors may benefit from anti-EGFR therapy. Clinical trial information: NCT02870920 .
Efficacy and safety of trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil monotherapy for refractory metastatic colorectal cancer: A retrospective study.
Authors: Rongrong Li, Hui-Jun Zhou, De-Yu Zeng, Shao-Feng Jiang, Wu Liu, Zhen-yang Liu
Journal: Journal of Clinical Oncology (2023)

e15562 Background: There had been no phase III trial to compare the efficacy between trifluridine/tipiracil (TAS-102) plus bevacizumab (BEV) with TAS-102 monotherapy in refractory metastatic colorectal cancer (mCRC). Our study sought to investigate the efficacy and safety of TAS-102 plus BEV versus TAS-102 monotherapy in these patients. Methods: We retrospectively analyzed the patients with refractory mCRC who received TAS-102 (35 mg/m2 twice daily; day 1–5 and 8–12; every 28 days) with or without BEV (5 mg/kg; day 1,15; every 28 days) between November 2020 and October 2022 in Hunan Cancer Hospital. All patients had previously received at least second-line treatment. The primary endpoint was overall survival (OS). Results: A total of 58 patients received TAS-102 plus BEV, and another 32 patients received TAS-102 monotherapy. With a median follow-up of 4.60 months (range, 0.20–22.80), the median overall survival (mOS) was 10.83 months [95% confidence interval (CI), 10.10–NA] for TAS-102 plus BEV, 7.43months (95% CI, 5.17–NA) for TAS-102 monotherapy. The hazard ratio (HR) was 0.90 (95% CI, 0.42–1.92), P= 0.78. Median progression-free survival (mPFS) was 4.67 months (95% CI, 3.57–7.37) for TAS-102 plus BEV, and 4.30 months (95% CI, 3.03–NA) for TAS-102 monotherapy. The HR was 1.04 (95% CI, 0.54–1.99), P= 0.91. The Cox multivariate regression analysis demonstrated that the patients who received treatment after TAS-102 with or without BEV(HR:0.25;95% CI, 0.09-0.71) and previously undergone Irinotecan (HR:0.23;95% CI, 0.06-0.95) were independent risk factors for OS and the patients who previously received Cetuximab was confirmed to have a significant better PFS(HR:0.17;95% CI, 0.03-0.91). Of the 70 patients who were evaluated, the TAS-102 plus BEV showed higher ORR and DCR than TAS-102 monotherapy, but the difference was not significant (ORR: 12.2% versus 0%; p= 0.16; and DCR: 77.5% versus 61.9%; p= 0.29). The incidence of platelet count decrease (grade ≥3) was significantly higher in the TAS-102 plus BEV group than the TAS-102 monotherapy group (3.00% vs. 0.00%, p = 0.03), whereas other adverse events were comparable between the two groups. Conclusions: Compared with TAS-102 monotherapy, TAS-102 plus BEV seemed to have comparable safety but improved disease control and prognosis in patients with refractory mCRC, although the difference was not significant. Further prospective studies are still needed to confirm our conclusions. [Table: see text]
Efficacy and safety of first-line immunotherapy for advanced gastric or gastroesophageal cancer: System review network meta-analysis.
Authors: Qiong Qin, Yongkun Sun, Lin Yang, Diansheng Zhong
Journal: Journal of Clinical Oncology (2023)

e16014 Background: In advanced gastric or gastroesophageal cancer, a series of randomized controlled trials had investigated different first-line immunotherapy compared with chemotherapy. However, the optimal immunotherapy strategy is yet to be established. We compared the efficacy and safety of first line immunotherapy for patients with advanced, HER2-negative gastric or gastroesophageal junction cancer. Methods: We performed systematic review and a network meta-analysis (NMA) of immune checkpoint inhibitors (ICIs) monotherapy or combined with chemotherapy for gastric or gastroesophageal cancer with HER2 negative. We searched PubMed, Embase, Cochrane Central Register of Controlled Trails, ClinicalTrials.gov, and several international conference databases, from 1 January 2012 to 1 March 2022.Published and unpublished randomized controlled trials compared different first-line immunotherapy with chemotherapy were included. This study was registered in the Prospective Register of Systematic Reviews (CRD 42021291609) to ensure transparency. Results: We analyzed a total 5 studies including 5279 patients and involving 5 immunotherapies. In patients without programmed death-ligand 1(PD-L1) selection, ICIs combined with chemotherapy improved progression free survival (PFS) and overall survival (OS). Sintilimab plus chemotherapy provided the best OS benefit (HR=0.77, 95% CI 0.63-0.94) and the best PFS benefit (HR=0.64, 95%CI 0.53-0.77) compared with standard chemotherapy. Furthermore, pembrolizumab plus chemotherapy seemed to provide the best objective response rate (OR= 1.81, 95%CI 1.44-2.28). Pembrolizumab monotherapy was the safest first-line treatment for grade equal or more 3 AEs (OR= 0.09, 95% CI 0.06-0.14). Subgroup analysis showed that sintilimab plus chemotherapy was associated with the best OS in CPS PD-L1≥1 (HR=0.73,95%CI 0.59-0.91) and PD-L1 ≥10 (HR=0.56, 95% CI 0.41-0.77). Pembrolizumab monotherapy improved OS in PD-L1 ≥10 (HR=0.69, 95% 0.49-0.97). Conclusions: Our results indicate that Sintilimab combined chemotherapy were associated with the best PFS and OS for patients with advanced GC or GEJC with HER2 negative.
IMpower010: Exploratory analysis of disease-free survival by KRAS status in patients with stage II-IIIA NSCLC treated with adjuvant atezolizumab vs best supportive care.
Authors: Martin Reck, Minu K Srivastava, Heather A. Wakelee, Enriqueta Felip, Nasser K. Altorki, Tibor Csoszi, Vladimir Moiseyenko, Andrey Akopov, Alexey Smolin, Antonio Chella, Eric Vallieres, Alex Martinez-Marti, Wei Zou, V. McNally, Elizabeth Bennett, Hen Prizant, Barzin Nabet, Marcus Ballinger, Barbara J. Gitlitz, Caicun Zhou
Journal: Journal of Clinical Oncology (2023)

8522 Background: The Phase III IMpower010 trial (NCT02486718) met its primary disease-free survival (DFS) endpoint leading to approval of atezolizumab after adjuvant platinum-based chemotherapy for completely resected PD-L1 TC ≥1% or ≥50% stage II-IIIA NSCLC in the US, EU and other regions. Mutant KRAS (mKRAS) is the most prevalent oncogenic driver in metastatic NSCLC (27% mKRAS [KRAS G12C,11%]; Osta et al, J Thorac Oncol 2019). Here, we report exploratory DFS outcomes by KRAS mutational status in patients from IMpower010. Methods: The study design and primary results of IMpower010 have been reported (Felip et al, Lancet 2021). After complete resection, patients received cisplatin-based doublet chemotherapy (1-4 21-day cycles) and were subsequently randomized to receive atezolizumab 1200 mg q3w (16 cycles) or best supportive care (BSC). This post hoc analysis evaluated DFS in subgroups of patients by KRAS mutational status. KRAS mutational status was assessed retrospectively using whole-exome sequencing (WES) on resected tumor tissue. Analyses were conducted in patients whose tumors harbored any mKRAS type, including G12C. A separate analysis of the KRAS G12C subgroup was not conducted due to limited patient numbers. Results: Of the 1005 patients in the intention-to-treat population (all randomized patients with stage IB-IIIA NSCLC), 603 comprised the WES biomarker-evaluable population (WES-BEP), and of these, 536 had stage II-IIIA NSCLC. Within the stage II-IIIA WES-BEP, the prevalence of mKRAS and KRAS G12C was 22% (n=118) and 10% (n=52), respectively. mKRAS was enriched in White, non-squamous and smoker populations. Atezolizumab showed DFS improvement vs BSC regardless of KRAS status in the stage II-IIIA WES-BEP (Table). In the mKRAS stage II-IIIA WES-BEP, atezolizumab showed DFS improvement vs BSC regardless of PD-L1 status. Conclusions: In IMpower010, the prevalence of mKRAS and KRAS G12C was similar to that seen in metastatic NSCLC. Despite limited patient numbers in this exploratory analysis, DFS appeared to be consistent and in favor of atezolizumab across subgroups regardless of KRAS status. Clinical trial information: NCT02486718 . [Table: see text]